tbuckley/cabot-search huggingface dataset:
Incorporating the HIV Infant Tracking System into standard-of-care early infant diagnosis of HIV services in Kenya: a cost-effectiveness analysis of the HITSystem randomised trial
Authors: Sarah Finocchario-Kessler, Kathy Goggin, Catherine Wexler, May Maloba, Brad Gautney, Samoel Khamadi, Raphael Lwembe, Shadrack Babu, Michael Sweat
Journal: The Lancet Global Health (2023)

The HITSystem efficacy trial showed significant improvements in early infant diagnosis retention, return and notification of infant test results, and earlier antiretroviral therapy (ART) initiation compared with standard-of-care early infant diagnosis services in Kenya. This study aimed to analyse data from the HITSystem trial to assess the cost-effectiveness of the intervention in Kenya.In this analysis, we extrapolated results from the HITSystem cluster randomised controlled trial to model early infant diagnosis outcomes and cost-effectiveness if the HITSystem was scaled up nationally in Kenya, compared with standard-of-care outcomes. We used a micro-costing method to collect cost data, which were analysed from a health-system perspective, reflecting the investment required to add HITSystem to existing early infant diagnosis services and infrastructure. The base model used to calculate cost-effectiveness was deterministic and calculated the progression of infants through early infant diagnosis. Differences in progression across study arms were used to establish efficacy outcomes. The number of life-years gained per infant successfully initiating ART were based on the Cost Effectiveness of Preventing AIDS Complications model in east Africa. HITSystem cost data were integrated into the model, and the incremental cost-effectiveness ratio was calculated in terms of cost per life-year gained. Sensitivity analyses were done using the deterministic model with triangular stochastic probability functions for key model parameters added. The number of life-years gained was discounted at 3% and costs were adjusted to 2021 values.The cost per life-year gained from the HITSystem was US$82·72. Total cost for national HITSystem coverage in Kenya was estimated to be around $2·6 million; covering 82 230 infants exposed to HIV at a cost of $31·38 per infant and a yield of 1133 infants receiving timely ART, which would result in 31 189 life-years gained. With sensitivity analyses, the cost per life-year gained varied from $40·13 to $215·05. 90% of model values across iterations ranged between $55·58 (lower 5% threshold) and $132·38 (upper 95% threshold).The HITSystem would be very cost-effective in Kenya and can optimise the return on the existing investment in the national early infant diagnosis programme.The US National Institute of Child Health and Human Development.
Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth
Authors: Matthew D. Taves, Shizuka Otsuka, Michaela A. Taylor, Kaitlynn M. Donahue, Thomas J. Meyer, Margaret C. Cam, Jonathan D. Ashwell
Journal: Journal of Clinical Investigation (2023)

Glucocorticoids are steroid hormones with potent immunosuppressive properties. Their primary source is the adrenals, where they are generated via de novo synthesis from cholesterol. In addition, many tissues have a recycling pathway in which glucocorticoids are regenerated from inactive metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by Hsd11b1). Here, we find that multiple tumor types express Hsd11b1 and produce active glucocorticoids. Genetic ablation of Hsd11b1 in such cells had no effect on in vitro growth, but reduced in vivo tumor progression, which corresponded with increased frequencies of CD8+ tumor-infiltrating lymphocytes (TILs) expressing activation markers and producing effector cytokines. Tumor-derived glucocorticoids were found to promote signatures of Treg activation and suppress signatures of conventional T cell activation in tumor-infiltrating Tregs. Indeed, CD8+ T cell activation was restored and tumor growth reduced in mice with Treg-specific glucocorticoid receptor deficiency. Importantly, pharmacologic inhibition of 11β-HSD1 reduced tumor growth to the same degree as gene knockout and rendered immunotherapy-resistant tumors susceptible to PD-1 blockade. Given that HSD11B1 expression is upregulated in many human tumors and that inhibition of 11β-HSD1 is well tolerated in clinical studies, these data suggest that targeting 11β-HSD1 may be a beneficial adjunct in cancer therapy.
Prevalence, risk factors and outcomes of cardiac disease in cystic fibrosis: a multinational retrospective cohort study
Authors: Freddy Frost, Dilip Nazareth, Laurent Fauchier, Dennis Wat, James Shelley, Philip Austin, Martin J. Walshaw, Gregory Y.H. Lip
Journal: European Respiratory Journal (2023)

Although people living with cystic fibrosis (PwCF) often have some risk factors for cardiovascular disease, including diabetes and chronic inflammation, little is known about the long-term cardiac risk in this condition. We aimed to determine the characteristics, rates and outcomes for cardiac disease in CF.
Cancer-Associated Fibroblast-Like Tumor Cells Remodel the Ewing Sarcoma Tumor Microenvironment
Authors: Emma D. Wrenn, April A. Apfelbaum, Erin R. Rudzinski, Xuemei Deng, Wei Jiang, Sudha Sud, Raelene A. Van Noord, Erika A. Newman, Nicolas M. Garcia, Aya Miyaki, Virginia J. Hoglund, Shruti S. Bhise, Sami B. Kanaan, Olivia G. Waltner, Scott N. Furlan, Elizabeth R. Lawlor
Journal: Clinical Cancer Research (2023)

Despite limited genetic and histologic heterogeneity, Ewing sarcoma (EwS) tumor cells are transcriptionally heterogeneous and display varying degrees of mesenchymal lineage specification in vitro. In this study, we investigated if and how transcriptional heterogeneity of EwS cells contributes to heterogeneity of tumor phenotypes in vivo.
Excitatory nucleo-olivary pathway shapes cerebellar outputs for motor control
Authors: Xiaolu Wang, Zhiqiang Liu, Milen Angelov, Zhao Feng, Xiangning Li, Anan Li, Yan Yang, Hui Gong, Zhenyu Gao
Journal: Nature Neuroscience (2023)

The brain generates predictive motor commands to control the spatiotemporal precision of high-velocity movements. Yet, how the brain organizes automated internal feedback to coordinate the kinematics of such fast movements is unclear. Here we unveil a unique nucleo-olivary loop in the cerebellum and its involvement in coordinating high-velocity movements. Activating the excitatory nucleo-olivary pathway induces well-timed internal feedback complex spike signals in Purkinje cells to shape cerebellar outputs. Anatomical tracing reveals extensive axonal collaterals from the excitatory nucleo-olivary neurons to downstream motor regions, supporting integration of motor output and internal feedback signals within the cerebellum. This pathway directly drives saccades and head movements with a converging direction, while curtailing their amplitude and velocity via the powerful internal feedback mechanism. Our finding challenges the long-standing dogma that the cerebellum inhibits the inferior olivary pathway and provides a new circuit mechanism for the cerebellar control of high-velocity movements.
The impact of steroid-sparing biologic therapies on weight loss in obese individuals with severe eosinophilic asthma
Authors: Alexandra M. Nanzer, Victoria Taylor, Andrew P. Hearn, Joanne E. Kavanagh, Tanya Patrick, Linda Green, Louise Thomson, Jodie Lam, Mariana Fernandes, Cris Roxas, Grainne d'Ancona, Brian D. Kent, Jaideep Dhariwal, David J. Jackson
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Frequent use of oral corticosteroids can lead to adverse consequences, including weight gain. Treatment with steroid-sparing anti-IL5/5R biologic therapies for severe asthma is associated with significant weight loss in obese patients.</b>https://bit.ly/3PyWRYj
Organizing memories for generalization in complementary learning systems
Authors: Weinan Sun, Madhu Advani, Nelson Spruston, Andrew Saxe, James E. Fitzgerald
Journal: Nature Neuroscience (2023)

Abstract Memorization and generalization are complementary cognitive processes that jointly promote adaptive behavior. For example, animals should memorize safe routes to specific water sources and generalize from these memories to discover environmental features that predict new ones. These functions depend on systems consolidation mechanisms that construct neocortical memory traces from hippocampal precursors, but why systems consolidation only applies to a subset of hippocampal memories is unclear. Here we introduce a new neural network formalization of systems consolidation that reveals an overlooked tension—unregulated neocortical memory transfer can cause overfitting and harm generalization in an unpredictable world. We resolve this tension by postulating that memories only consolidate when it aids generalization. This framework accounts for partial hippocampal–cortical memory transfer and provides a normative principle for reconceptualizing numerous observations in the field. Generalization-optimized systems consolidation thus provides new insight into how adaptive behavior benefits from complementary learning systems specialized for memorization and generalization.
Considerations for patient and public involvement and engagement in health research
Authors: Olalekan Lee Aiyegbusi, Christel McMullan, Sarah E. Hughes, Grace M. Turner, Anuradhaa Subramanian, Richard Hotham, Elin Haf Davies, Chris Frost, Yvonne Alder, Lisa Agyen, Lewis Buckland, Jennifer Camaradou, Amy Chong, Felicity Jeyes, Sumita Kumar, Karen L. Matthews, Patricia Moore, Jane Ormerod, Gary Price, Michael Saint-Cricq, David Stanton, Anita Walker, Shamil Haroon, Alastair K. Denniston, Melanie J. Calvert, Kirsty Brown, Joht Singh Chandan, Georgios V. Gkoutos, Louise J. Jackson, Janet M. Lord, Tom Marshall, Steven Marwaha, Puja Myles, Krishnarajah Nirantharakumar, Samantha Cruz Rivera, Elizabeth Sapey, Nikita Simms-Williams, Tim Williams, David C. Wraith
Journal: Nature Medicine (2023)
Confounding cannot be ignored in any observational design
Authors: Ramesh Kumar
Journal: European Respiratory Journal (2023)

A group of researchers revealed a strong correlation between the sales of ice cream and the number of deaths by drowning, and asserted that they searched the data and did not discover any confounding variables. They went on to conclude that the relationship was causal, indicating that ice cream sales could be altered to reduce the number of drowning incidents. Most readers concurred with the researchers, given the gravity of drowning, and enthusiastically endorsed the study. Confounding cannot be ignored in any observational design: comment on the ERJ paper by C.J. Reynolds and co-workers <https://bit.ly/3oueVrx>
L-GIREMI uncovers RNA editing sites in long-read RNA-seq
Authors: Zhiheng Liu, Giovanni Quinones-Valdez, Ting Fu, Elaine Huang, Mudra Choudhury, Fairlie Reese, Ali Mortazavi, Xinshu Xiao
Journal: Genome biology (2023)

Abstract Although long-read RNA-seq is increasingly applied to characterize full-length transcripts it can also enable detection of nucleotide variants, such as genetic mutations or RNA editing sites, which is significantly under-explored. Here, we present an in-depth study to detect and analyze RNA editing sites in long-read RNA-seq. Our new method, L-GIREMI, effectively handles sequencing errors and read biases. Applied to PacBio RNA-seq data, L-GIREMI affords a high accuracy in RNA editing identification. Additionally, our analysis uncovered novel insights about RNA editing occurrences in single molecules and double-stranded RNA structures. L-GIREMI provides a valuable means to study nucleotide variants in long-read RNA-seq.
Impact and cost-effectiveness of short-course tuberculosis preventive treatment for household contacts and people with HIV in 29 high-incidence countries: a modelling analysis
Authors: Theresa Ryckman, Jeff Weiser, Makaita Gombe, Karin Turner, Priyanka Soni, Dessislava Tarlton, Nargiza Mazhidova, Gavin Churchyard, Richard E Chaisson, David W Dowdy
Journal: The Lancet Global Health (2023)
2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines
Authors: Salim S. Virani, L. Kristin Newby, Suzanne V. Arnold, Vera Bittner, LaPrincess C. Brewer, Susan Halli Demeter, Dave L. Dixon, William F. Fearon, Beverly Hess, Heather M. Johnson, Dhruv S. Kazi, Dhaval Kolte, Dharam J. Kumbhani, Jim LoFaso, Dhruv Mahtta, Daniel B. Mark, Margo Minissian, Ann Marie Navar, Amit R. Patel, Mariann R. Piano, Fatima Rodriguez, Amy W. Talbot, Viviany R. Taqueti, Randal J. Thomas, Sean van Diepen, Barbara Wiggins, Marlene S. Williams
Journal: Circulation (2023)

AIM: The “2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease” provides an update to and consolidates new evidence since the “2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease” and the corresponding “2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease.” METHODS: A comprehensive literature search was conducted from September 2021 to May 2022. Clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants were identified that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE: This guideline provides an evidenced-based and patient-centered approach to management of patients with chronic coronary disease, considering social determinants of health and incorporating the principles of shared decision-making and team-based care. Relevant topics include general approaches to treatment decisions, guideline-directed management and therapy to reduce symptoms and future cardiovascular events, decision-making pertaining to revascularization in patients with chronic coronary disease, recommendations for management in special populations, patient follow-up and monitoring, evidence gaps, and areas in need of future research. Where applicable, and based on availability of cost-effectiveness data, cost–value recommendations are also provided for clinicians. Many recommendations from previously published guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.
The predominant PAR4 variant in individuals of African ancestry worsens murine and human stroke outcomes
Authors: Frederik Denorme, Nicole D. Armstrong, Michelle L. Stoller, Irina Portier, Emilia A. Tugolukova, Rikki M. Tanner, Emilie Montenont, Seema Bhatlekar, Mark Cody, John L. Rustad, Abigail Ajanel, Neal D. Tolley, Darian C. Murray, Julie L. Boyle, Marvin T. Nieman, Steven E. McKenzie, Christian Con Yost, Leslie A. Lange, Mary Cushman, Marguerite R. Irvin, Paul F. Bray, Robert A. Campbell
Journal: Journal of Clinical Investigation (2023)

Protease activated receptor (PAR) 4 (gene: F2RL3) harbors a functional dimorphism, rs773902 A/G (encoding Thr120/Ala120, respectively) and is associated with greater platelet aggregation. The A allele frequency is more common in Black individuals, and Black individuals have a higher incidence of ischemic stroke than White individuals. However, it is not recognized whether the A allele is responsible for worse stroke outcomes. To directly test the in vivo effect of this variant on stroke, we generated mice where F2rl3 was replaced by F2RL3, thereby expressing human PAR4 (hPAR4) with either Thr120 or Ala120. Compared to hPAR4 Ala120 mice, hPAR4 Thr120 mice had worse stroke outcomes, mediated in part by enhanced platelet activation and platelet-neutrophil interactions. Analyses of 7620 Black subjects with 487 incident ischemic strokes demonstrated the AA genotype was a risk for incident ischemic stroke and worse functional outcomes. In humanized mice, ticagrelor with or without aspirin improved stroke outcomes in hPAR4 Ala120 mice, but not in hPAR4 Thr120 mice. P-selectin blockade improved stroke outcomes and reduced platelet-neutrophil interactions in hPAR4 Thr120 mice. Our results may explain some of the racial disparity in stroke and support the need for studies of non-standard anti-platelet therapies for patients expressing PAR4 Thr120.
Predicting steroid responsiveness using airway smooth muscle in COPD: a HISTORIC study
Authors: Janice M. Leung, Don D. Sin
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>The airway smooth muscle layer is a dynamic inflammatory environment, which may explain why, in COPD, patients with increased airway smooth muscle area may respond well to inhaled corticosteroids</b>https://bit.ly/3oZQK4J
Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer
Authors: Yeon Hee Park, Seock-Ah Im, Kyunghee Park, Ji Wen, Kyung-Hun Lee, Yoon-La Choi, Won-Chul Lee, Ahrum Min, Vinicius Bonato, Seri Park, Sripad Ram, Dae-Won Lee, Ji-Yeon Kim, Su Kyeong Lee, Won-Woo Lee, Jisook Lee, Miso Kim, Hyun Seon Kim, Scott L. Weinrich, Han Suk Ryu, Tae Yong Kim, Stephen Dann, Yu-Jin Kim, Diane R. Fernandez, Jiwon Koh, Shuoguo Wang, Song Yi Park, Shibing Deng, Eric Powell, Rupesh Kanchi Ravi, Jadwiga Bienkowska, Paul A. Rejto, Woong-Yang Park, Zhengyan Kan
Journal: Genome Medicine (2023)

Abstract Background Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2− MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. Methods Tissue was collected from 89 patients with HR+/HER2− MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. Results Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1 , ESR1, PTEN , and KMT2C . Conclusions We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. Trial registration ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.
Management of Stage III Non–Small-Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update
Authors: Navneet Singh, Megan E. Daly, Nofisat Ismaila, Megan E. Daly, Navneet Singh, Mara B. Antonoff, Douglas A. Arenberg, Jeffrey Bradley, Elizabeth David, Frank Detterbeck, Martin Früh, Matthew A. Gubens, Amy C. Moore, Sukhmani K. Padda, Jyoti D. Patel, Tanyanika Phillips, Angel Qin, Clifford Robinson, Charles B. Simone
Journal: Journal of Clinical Oncology (2023)

ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in theASCO Guideline Methodology Manual.The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options. See the Appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only).
No evidence of durable trained immunity after two doses of adenovirus-vectored or mRNA COVID-19 vaccines
Authors: Natalie E. Stevens, Feargal J. Ryan, Nicole L. Messina, Stephen J. Blake, Todd S. Norton, Susie Germano, Jane James, Georgina L. Eden, Yee C. Tee, Miriam A. Lynn, Rochelle Botten, Simone E. Barry, Nigel Curtis, David J. Lynn
Journal: Journal of Clinical Investigation (2023)
Spatial Profiling of Circular RNAs in Cancer Reveals High Expression in Muscle and Stromal Cells
Authors: Juan L. García-Rodríguez, Ulrik Korsgaard, Ulvi Ahmadov, Morten T. Jarlstad Olesen, Kim-Gwendolyn Dietrich, Emma B. Hansen, Stine M. Vissing, Benedichte P. Ulhøi, Lars Dyrskjøt, Karina D. Sørensen, Jørgen Kjems, Henrik Hager, Lasse S. Kristensen
Journal: Cancer Research (2023)

Circular RNAs (circRNA) are covalently closed molecules that can play important roles in cancer development and progression. Hundreds of differentially expressed circRNAs between tumors and adjacent normal tissues have been identified in studies using RNA sequencing or microarrays, emphasizing a strong translational potential. Most previous studies have been performed using RNA from bulk tissues and lack information on the spatial expression patterns of circRNAs. Here, we showed that the majority of differentially expressed circRNAs from bulk tissue analyses of colon tumors relative to adjacent normal tissues were surprisingly not differentially expressed when comparing cancer cells directly with normal epithelial cells. Manipulating the proliferation rates of cells grown in culture revealed that these discrepancies were explained by circRNAs accumulating to high levels in quiescent muscle cells due to their high stability; on the contrary, circRNAs were diluted to low levels in the fast-proliferating cancer cells due to their slow biogenesis rates. Thus, different subcompartments of colon tumors and adjacent normal tissues exhibited striking differences in circRNA expression patterns. Likewise, the high circRNA content in muscle cells was also a strong confounding factor in bulk analyses of circRNAs in bladder and prostate cancers. Together, these findings emphasize the limitations of using bulk tissues for studying differential circRNA expression in cancer and highlight a particular need for spatial analysis in this field of research.The abundance of circRNAs varies systematically between subcompartments of solid tumors and adjacent tissues, implying that differentially expressed circRNAs discovered in bulk tissue analyses may reflect differences in cell type composition between samples.
Further 100 000 appointments cancelled during latest strike action by junior doctors
Authors: Gareth Iacobucci
Journal: BMJ (2023)

There were 101 977 acute inpatient and outpatient appointments cancelled during the latest round of strike action by junior doctors in England, NHS data 1 show.Overall, more than three quarters of a million (754 555) appointments across acute, mental health, ambulance, and community services have had to be rescheduled because of industrial action since last December, including 698 813 inpatient and outpatient appointments.